D-homo oxasteroids

ABSTRACT

Steroids having the formula ##STR1## or the 1,2-dehydro derivative thereof, wherein R 1  is hydrogen, acyloxy, halogen, or hydroxy; R 2  is hydrogen or alkyl; R 3  is alkyl; R 4  is carbonyl, β-hydroxymethylene, β-chloromethylene or β-bromomethylene; R 5  is hydrogen, fluorine, chlorine or bromine; R 6  is hydrogen, fluorine or methyl; and R 7  is hydrogen, chlorine or bromine; can be used as antiinflammatory agents.

BACKGROUND OF THE INVENTION

German Offenlegungsschrift No. 2,526,788 published Dec. 23, 1976discloses that the oxidation of certain 17-alkanoyloxy-Δ¹⁶ -steroidswith osmium tetroxide opens the D-ring of the steroids yielding a16,17-seco-steroid of the type ##STR2## wherein "St" symbolizes A, B andC rings of the steroid and R symbolizes methyl or ethyl. Ring closure ofthe 16,17-seco-steroid pictured above yields a D-homo-oxasteroid of thetype ##STR3## Subsequent treatment of the 17-oxa-17a-oxo-D-homo-steroidyields a steroid of the type ##STR4##

Ozonolysis of certain 17-acetoxy-Δ¹⁶ -estrenes followed by ring closure(using p-toluenesulfonic acid) of the resulting seco-steroids, is taughtby Baran in U.S. Pat. No. 3,257,412 to yield 17-oxo-D-homoestrenes.

Iriarte et al., J. C. S. Chem. Comm., 1110 (1972), describe the osmiumtetroxide oxidation and subsequent periodic oxidation of the enolacetate having the structure ##STR5## to yield a compound having thestructure ##STR6##

Kuo et al., J. Org. Chem., 28, 1619 (1963), describe the preparation ofa 17-oxa-D-homopregnane having the structure ##STR7##

SUMMARY OF THE INVENTION

Steroids having the formula ##STR8## can be used as antiinflammatoryagents.

In formula I, and throughout the specification, the symbols are asdefined below:

R₁ is hydrogen, acyloxy (i.e., ##STR9## wherein Y is alkyl or aryl),halogen or hydroxy; R₂ is hydrogen or alkyl;

R₃ is alkyl;

R₄ is carbonyl, β-hydroxymethylene, β-chloromethylene, orβ-bromomethylene;

R₅ is hydrogen, fluorine, chlorine or bromine;

R₆ is hydrogen, fluorine or methyl; and

R₇ is hydrogen, chlorine or bromine; with the proviso that if R₁ ishydroxy, R₂ is alkyl; and with the further proviso that if R₂ is alkyl,it is the same alkyl group as R₃. A dotted line in the 1,2 position of astructural formula in this disclosure indicates the optional presence ofethylenic unsaturation.

The term "aryl", as used throughout the specification, refers to phenylor phenyl substituted with one or two alkyl, alkoxy or halogen groups.

The term "halogen", as used throughout the specification, refers tofluorine, chlorine, bromine or iodine.

The terms "alkyl" and "alkoxy", as used throughout the specification,refer to groups having 1 to 10 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

The D-homo oxasteroids of this invention, wherein R₁ is hydrogen,acyloxy or halogen (this subgrouping of substituents is hereinafterreferred to as "R'₁ ") and R₂ is hydrogen, can be prepared by reactingthe corresponding Δ¹⁶ -pregnene having the formula ##STR10## with ozone,and an alkanol having the formula

    R.sub.3 --OH,                                              (III)

and then treating the reaction mixture with a reducing agent, e.g., adialkylsulfide such as dimethylsulfide, in an organic solvent, e.g., ahalogenated hydrocarbon such as dichloromethane. The steroid product hasthe formula ##STR11## The above-described reaction is a novel one, andas such, it constitutes an integral part of this invention.

Reaction of a steroid product of formula IV with an alkanol in thepresence of an acid catalyst, e.g., p-toluene-sulfonic acid, yields thecorresponding product having the formula ##STR12## if carried out at anelevated temperature, preferably under reflux conditions.

Saponification of a steroid of formula V, wherein R'₁ is acyloxy, yieldsthe corresponding 21-hydroxy steroid having the formula ##STR13## Thesaponification reaction is run in the presence of a base, e.g., analkali metal carbonate, and can be carried out in an organic solvent,e.g., an alkanol.

Many alternative processes are available for the preparation of thesteroids of this invention. For example, the steroids of formula Ihaving a halogen substituent in the 21-position can be prepared from thecorresponding 21-hydroxy steroids via the 21-mesylate. Another exampleinvolves the trans-etherification of a steroid of formula IV. In someinstances, a steroid of formula IV, especially one with a large,sterically hindered R₃ group (e.g., isopropyl or t-butyl) can beprepared by reacting a steroid of formula IV with the appropriatealkanol, in the presence of an acid catalyst at room temperature.

Steroids having the formula ##STR14## are contemplated as a sub-genuswithin the broader genus of formula I.

In some instances, the preparation of the steroids of formula I willyield a solvate of the steroid, rather than the steroid per se. Thesesolvates are also contemplated as a part of this invention.

The steroids of formula I can be used in lieu of known glucocorticoidsin the treatment of inflammatory conditions; e.g., rheumatoid arthritis.They can be administered in the same manner as hydrocortisone, thedosage being adjusted for the relative potency of the particularsteroid. Additionally, the steroids of this invention can be usedtopically in lieu of known glucocorticoids in the treatment of skinconditions such as dermatitis, psoriasis, sunburn, neurodermatitis,eczema or anogenital pruritus.

When given orally, the steroids of this invention may be used in adosage range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams,for a 70 kg. mammal. If administered topically, the steroids of thisinvention may be used in the range of 0.01 to 5.0% by weight, preferably0.05 to 2.0% by weight, in a conventional cream, ointment, lotion or thelike.

The following examples are specific embodiments of this invention.

EXAMPLE 121-(Acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 805 mg of21-(acetyloxy)-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione in 30ml of 2:1 dichloromethane-methanol is cooled to -78° C. and a stream ofozone in oxygen passed through (0.00225 moles). An amount of 2 ml (largeexcess) of dimethylsulfide is added, the solution is kept for 2 hours atambient temperature and the solvents are then evaporated in vacuo. Asolution of the residue in chloroform is washed with water, dried, andchromatographed on a 60 g-silica gel column. Elution with 3:1chloroform-ethyl acetate gives 605 mg of crude product that crystallizesfrom acetone-hexane to give 340 mg of material, melting point 170°-172°C., dec. Two recrystallizations from methanol give 195 mg of product,melting point 170°-172° C., dec.

Anal. Calc'd. for C₂₄ H₃₁ FO₈ : C, 61.78; H, 6.69; F, 4.07.

Found: C, 62.00; H, 6.90; F, 4.25.

EXAMPLE 221-Chloro-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregn-4-ene-3,20-dione

A solution of 1.36 g of21-chloro-9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione in 30 ml of2:1 dichloromethane-methanol is cooled to -78° C. and a stream of ozonein oxygen (0.00397 mole) passed through for 11 minutes. Severalmilliliters (large excess) of dimethylsulfide are added and the solutionis allowed to warm to ambient temperature. After 210 minutes, thesolvents are removed in vacuo and the residue dissolved in chloroform,washed with water, dried and applied on a 40 g-silica gel column.Elution with chloroform gives 1.03 g of product that crystallizes frommethanol to give 400 mg of solid in two crops. A furtherrecrystallization from methanol gives 304 mg of product, melting point160°-162° C., dec.

Anal. Calc'd. for C₂₂ H₃₀ ClFO₆ : C, 59.39; H, 6.80; Cl, 7.97; F, 4.27.

Found: C, 59.49; H, 7.00; Cl, 8.06; F, 4.00.

EXAMPLE 321-(Acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregn-4-ene-3,20-dione,methanol solvate (1:1)

A solution of 5.0 g of21-(acetyloxy)-9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione in amixture of 100 ml of dichloromethane and 40 ml of methanol is cooled to-78° C. and a stream of ozone in oxygen (0.0133 mole) passed through.The solution is treated with 5 ml of dimethylsulfide and allowed to warmto ambient temperature. The solvents are removed in vacuo and a solutionof the residue in chloroform is washed with water, dried, andchromatographed on a 50 g-silica gel column. Elution with chloroformgives 4.7 g of material which crystallizes from methanol to give 2.13 gof substantially pure material. Two recrystallizations of 1 g of thismaterial give 705 mg of the title methanol solvate.

Anal. Calc'd. for C₂₅ H₃₇ FO₉ : C, 59.98; H, 7.45; F, 3.79.

Found: C, 59.37; H, 7.55; F, 3.79.

EXAMPLE 421-(Acetyloxy)-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione

A solution of 1.615 g of21-(acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregn-4-ene-3,20-dione,methanol solvate (1:1) (see Example 3) in 50 ml of ethanol is refluxedwith 100 mg of p-toluenesulfonic acid for 1 hour, cooled, and dilutedwith water. The resulting solution is extracted with chloroform, and thechloroform extract washed with 5% sodium bicarbonate solution and water,dried, and evaporated. The residue is dissolved in chloroform andchromatographed on a 50 g-silica gel column. Elution with chloroformgives 1.37 g of material which crystallizes from ether-hexane to give785 mg of product, melting point 220°-222° C.

Anal. Calc'd. for C₂₇ H₃₉ FO₈ : C, 63.51; H, 7.70; F, 3.72.

Found: C, 63.77; H, 7.80; F, 3.46.

EXAMPLE 516β,17a-Diethoxy-9-fluoro-11β,21-dihydroxy-D-homo-17-oxapregn-4-ene-3,20-dione

A solution of 378 mg of21-(acetyloxy)-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione(see Example 4) in 15 ml of methanol is stirred at 0° C. with 1.5 ml of10% potassium carbonate solution under nitrogen for 1 hour; stirred 1hour at room temperature; and stirred 30 minutes at 70° C. The resultingsolution is cooled, diluted with water and extracted with chloroform.The chloroform solution is dried and evaporated to give 291 mg of thetitle compound.

EXAMPLE 621-Chloro-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione(A)16β,17a-Diethoxy-9-fluoro-11β-hydroxy-21-(mesyloxy)-D-homo-17-oxapregn-4-ene-3,20-dione

A solution of 740 mg of16β,17a-diethoxy-9-fluoro-11β,21-dihydroxy-D-homo-17-oxapregn-4-ene-3,20-dione(see Example 5) in 10 ml of pyridine is stirred at 0° C. with 0.2 ml ofmethanesulfonyl chloride for 2 hours. The solution is poured into cold2N hydrochloric acid and the resulting solid filtered. Attemptedpurification by preparative thin-layer chromatography (TLC) fails. Theresulting 601 mg of material is dissolved in pyridine and stirred forabout 16 hours with excess methanesulfonyl chloride at 5° C. Afterworkup as above (see Example 5) the solid is dissolved in chloroform andchromatographed on a 40 g-silica gel column. Elution with chloroformgives 361 mg of TLC pure mesylate.

(B)21-Chloro-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione

A solution of 361 mg of the above mesylate in 25 ml of dimethylformamideis refluxed with 3.0 g of lithium chloride for 30 minutes undernitrogen. The solution is cooled to room temperature, diluted withwater, and the resulting solid filtered. The solid is dissolved inchloroform and chromatographed on a 20 g-silica gel column. Elution withchloroform gives 175 mg of material which crystallizes from methanol togive 123 mg of TLC pure material, melting point 206°-208° C., dec.

Anal. Calc'd. for C₂₅ H₃₆ ClFO₆ : C, 61.65; H, 7.45; Cl, 7.28; F, 3.90.

Found: C, 61.85; H, 7.62; Cl, 7.17; F, 4.18.

EXAMPLE 721-Chloro-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.9 g of21-chloro-9-fluoro-11β-hydroxy-pregna-1,4,16-triene-3,20-dione in 100 mlof dichloromethane and 50 ml of ethanol is cooled to -78° C. and a 10%excess of ozone in oxygen passed through. The solution is treated with 5ml of dimethylsulfide and allowed to warm to ambient temperature andstand for about 16 hours. The solvents are evaporated and a chloroformsolution of the residue is washed with water, dried, and evaporated. Theresidue is dissolved in chloroform and chromatographed on a 40 g-silicagel column. Elution with chloroform and then chloroform-ethyl acetate(5:1) gives TLC pure material that crystallizes frommethanol-dichloromethane to give 563 mg, melting point 171°-173° C.

Anal. Calc'd. for C₂₃ H₃₀ ClFO₆ : C, 60.45; H, 6.62; Cl, 7.76; F, 4.12.

Found: C, 60.34; H, 6.60; Cl, 7.62; F, 4.37.

EXAMPLE 821-Chloro-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.9 g of21-chloro-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione in 100 mlof dichloromethane and 50 ml of methanol is cooled to -78° C. and a 10%excess of ozone in oxygen passed through. After addition of 5 ml ofdimethylsulfide the solution is allowed to warm to room temperature andstirred for about 16 hours. The solvents are removed in vacuo and anethyl acetate solution of the residue is washed with water, dried, andevaporated to give a solid. Recrystallization frommethanol-dichloromethane gives 925 mg of product, melting point181°-183° C.

Anal. Calc'd. for C₂₂ H₂₈ ClFO₆ : C, 59.66; H, 6.37; Cl, 8.06; F. 4.29.

Found: C, 59.78; H, 6.62; Cl, 7.82; F, 4.51.

EXAMPLE 921-Chloro-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregna-1,4diene-3,20-dione

A solution of 787 mg of21-chloro-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 7) in 50 ml of ethanol is refluxed with 100 mg ofp-toluene-sulfonic acid for 1 hour. The solution is cooled, poured into450 ml of water, stirred for 15 minutes, and filtered. The resultingsolid is recrystallized from methanol-dichloromethane to give 550 mg ofproduct, melting point 218°-220° C., dec.

Anal. Calc'd. for C₂₅ H₃₄ ClFO₆ : C, 61.91; H, 7.07; Cl, 7.31; F, 3.92.

Found: C, 62.20; H, 7.21; Cl, 7.13; F, 4.16.

EXAMPLE 1021-Chloro-9-fluoro-11β-hydroxy-16β,17a-dimethoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.314 g of21-chloro-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 7) in 50 ml of methanol is refluxed for 90 minutes with 100mg of p-toluenesulfonic acid. The solution is poured into cold water andextracted with ethyl acetate to give the crude product. Crystallizationfrom methanol-dichloromethane gives 582 mg of product, melting point228°-230° C., dec.

Anal. Calc'd. for C₂₃ H₃₀ ClFO₆ : C, 60.45; H, 6.62; Cl, 7.76; F, 4.12.

Found: C, 60.49; H, 6.64; Cl, 7.86; F, 4.26.

EXAMPLE 1121-(Acetyloxy)-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 4.02 g of21-(acetyloxy)-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione in100 ml of dichloromethane and 50 ml of ethanol is cooled to -78° C. anda 10% excess of ozone in oxygen is passed through. After addition of 5ml of dimethylsulfide the solution is allowed to warm to roomtemperature over about a 16-hour period. The solvents are evaporated anda solution of the residue in ethyl acetate is washed with water, dried,and evaporated. Crystallization from ethanol-dichloromethane gives 2.72g of material, melting point 168°-170° C., dec.

Anal. Calc'd. for C₂₅ H₃₃ FO₈ : C, 62.49; H, 6.92; F, 3.95.

Found: C, 62.55; H, 6.92; F, 3.88.

EXAMPLE 1221-(Acetyloxy)-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.2 g. of21-(acetyloxy)-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 11) in 50 ml of ethanol is refluxed for 90 minutes with 100mg of p-toluenesulfonic acid. The mixture is cooled, poured intoice-water and extracted with ethyl acetate to give 1.0 g of solid. Thisis combined with 1.2 g of similar material, dissolved in chloroform andchromatographed on a 60 g-silica gel column. Elution with chloroformgives 1.75 g of TLC pure solid. Crystallization frommethanol-dichloromethane gives 1.35 g of product, melting point223°-225° C. (foams and resolidifies at 120° C.).

Anal. Calc'd. for C₂₇ H₃₇ FO₈ : C, 63.76; H, 7.33; F, 3.74.

Found: C, 63.61; H, 7.10; F, 3.92.

EXAMPLE 1321-(Acetyloxy)-9-fluoro-11β-hydroxy-16β,17a-dimethoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 5.15 g of21-(acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 1) in 100 ml of methanol is refluxed for 90 minutes with200 mg of p-toluenesulfonic acid. The solution is poured into water andthe resulting solid filtered. The solid is dissolved in dichloromethane,dried, and chromatographed on a 60 g-silica gel column. Elution withchloroform gives 2.1 g of material which is a mixture of isomers by tlcand nmr. This material is crystallized from acetone-hexane to give 738mg of a mixture. The mother liquor is evaporated and crystallized frommethanol twice to give 455 mg of product, melting point 225°-227° C.

Anal. Calc'd. for C₂₅ H₃₃ FO₈ : C, 62.49; H, 6.92; F, 3.95.

Found: C, 62.41; H, 7.04; F, 4.20.

EXAMPLE 1421-Chloro-16β-(1,1-dimethylethoxy)-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.9 g of21-chloro-9-fluoro-11β-hydroxy-pregna-1,4,16-triene-3,20-dione in 120 mlof dichloromethane and 30 ml of t-butanol is cooled to -78° C. and a 10%excess of ozone in oxygen passed through. After addition of 5 ml ofdimethylsulfide the solution is allowed to warm to room temperature andstirred for about 16 hours. The solvents are removed in vacuo and theresidue dissolved in ethyl acetate, washed with water, dried, andevaporated. The residue is dissolved in chloroform and chromatographedon a 20 g-silica gel column. Elution with chloroform gives 1.15 g ofmaterial. Several crystallizations from methanol-dichloromethane give365 mg of product, melting point 170°-173° C.

Anal. Calc'd. for C₂₅ H₃₄ ClFO₆ : C, 61.91; H, 7.07; Cl, 7.31; F, 3.92.Found: C, 61.79; H, 7.37; Cl, 7.02; F, 3.95.

EXAMPLE 1521-Chloro-9-fluoro-11β-hydroxy-16β,17a-bis-(1-methylethoxy)-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.85 g of21-chloro-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 7) in 50 ml of isopropanol is refluxed for 30 minutes with180 mg of p-toluenesulfonic acid. The solution is diluted with water andextracted with ethyl acetate to give the crude product. This isdissolved in chloroform and chromatographed on a silica gel column togive 713 mg of the title compound after crystallization from methanol.This is combined with 545 mg of similar material for characterization;melting point 195°-197° C., dec.

Anal. Calc'd. for C₂₇ H₃₈ ClFO₆ : C, 63.21; H, 7.47; Cl, 6.91; F, 3.70.Found: C, 63.25; H, 7.69; Cl, 6.81; F, 3.99.

EXAMPLE 1621-Chloro-9-fluoro-11β,17a-dihydroxy-16β-(1-methylethoxy)-D-homo-17-oxapregna-1,4-diene-3,20-dione

A solution of 1.63 g of21-chloro-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione(see Example 7) in 400 ml of isopropanol is stirred for 3.5 days with500 mg of p-toluenesulfonic acid. The solution is poured into 2 litersof water and extracted with ethyl acetate to give 1.61 g of solid. Thisis triturated with dichloromethane and filtered to give 782 mg of TLCpure material. The filtrate is chromatographed on a 30 g-silica gelcolumn to give a further 400 mg. These are combined and recrystallizedfrom methanol to give 844 mg of product, melting point 238°-240° C.

Anal. Calc'd. for C₂₄ H₃₂ ClFO₆ : C, 61.34; H, 6.65; Cl, 7.55; F, 4.04.Found: C, 61.54; H, 6.93; Cl, 7.37; F, 4.19.

EXAMPLES 17-24

Following the procedures of Example 1, but substituting the steroidlisted in column I for21-(acetyloxy)-9-fluoro-11β-hydroxypregn-1,4,16-triene-3,20-dione yieldsthe steroid listed in column II.

    __________________________________________________________________________           Column I                Column II                                      __________________________________________________________________________    21-(acetyloxy)-6α,9-difluoro-11β-hydroxy-                                                  21-(acetyloxy)-6α,9-difluoro-11β,17a-di                            hydroxy-                                              pregna-1,4,16-triene-3,20-dione                                                                       16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,2                            0-                                                                            dione                                                 9-fluoro-11β-hyroxy-6α-methylpregna-1,4,16-                                                9-fluoro-11β,17a-dihydroxy-16β-methoxy-6                            α-methyl-                                       triene-3,20-dione       D-homo-17-oxapregna-1,4-diene-3,20-dione              11β-hydroxypregna-4,16-diene-3,20-dione                                                          11β,17a-dihydroxy-16β-methoxy-D-homo-17-                            oxapregn-                                                                     4-ene-3,20-dione                                      21-(acetyloxy)-2-chloro-6α,9-difluoro-11β-                                                 21-(acetyloxy)-2-chloro-6α,9-difluoro-11.bet                            a.,17a-                                               hydroxypregna-1,4,16-triene-3,20-dione                                                                dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4                            -                                                                             diene-3,20-dione                                      21-(acetyloxy)-2-bromo-6α,9-difluoro-11β-                                                  21-(acetyloxy)-2-bromo-6α,9-difluoro-11.beta                            .,17a-                                                hydroxypregna-1,4,16-triene-3,20-dione                                                                dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4                            -                                                                             diene-3,20-dione                                      21-(acetoxy)-9,11β-dichloropregna-1,4,16-                                                        21-(acetyloxy)-9,11β-dichloro-17a-hydroxy-16.                            beta.-                                                triene-3,20-dione       methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione      21-(acetyloxy)-9,11β-dibromopregna-1,4,16-                                                       21-(acetyloxy)-9,11β-dibromo-17a-hydroxy-16.b                            eta.-                                                 triene-3,20-dione       methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione      21-(acetyloxy)-9-bromo-11β-chloropregna-                                                         21-(acetyloxy)-9-bromo-11β-chloro-17a-hydroxy                            -                                                     1,4,16-triene-3,20-dione                                                                              16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,2                            0-dione                                               __________________________________________________________________________

What is claimed is:
 1. A steroid having the formula, ##STR15## or the1,2-dehydro derivative thereof; wherein R₁ is hydrogen, ##STR16##halogen or hydroxy; R₂ is hydrogen or alkyl; R₃ is alkyl; R₄ iscarbonyl, β-hydroxymethylene, β-chloromethylene or β-bromomethylene; R₅is hydrogen, fluorine, chlorine or bromine; R₆ is hydrogen, fluorine ormethyl; and R₇ is hydrogen, chlorine or bromine; with the proviso thatwhen R₁ is hydroxy, R₂ is alkyl; and with the further proviso that whenR₂ is alkyl, it is the same alkyl group as R₃ ; wherein aryl is phenylor phenyl substituted with one or two alkyl, alkoxy or halogen groups;and alkyl and alkoxy are groups having 1 to 10 carbon atoms.
 2. Asteroid in accordance with claim 1 wherein R₆ and R₇ are hydrogen.
 3. Asteroid in accordance with claim 2 wherein R₂ is hydrogen.
 4. A steroidin accordance with claim 2 wherein R₂ is alkyl.
 5. A steroid inaccordance with claim 2 wherein R₄ is β-hydroxymethylene.
 6. A steroidin accordance with claim 1 wherein R₁ is ##STR17##
 7. A steroid inaccordance with claim 1 wherein R₁ is halogen.
 8. A steroid inaccordance with claim 1 wherein R₁ is hydroxy.
 9. A steroid inaccordance with claim 1 having the formula ##STR18## or the 1,2-dehydroderivative thereof.
 10. A steroid in accordance with claim 9,21-(acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.11. A steroid in accordance with claim 9,21-chloro-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregn-4-ene-3,20-dione.12. A steroid in accordance with claim 9,21-(acetyloxy)-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregn-4-ene-3,20-dione.13. A steroid in accordance with claim 9,21-(acetyloxy)-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione.14. A steroid in accordance with claim 9,16β,17a-diethoxy-9-fluoro-11β,21-dihydroxy-D-homo-17-oxapregn-4-ene-3,20-dione.15. A steroid in accordance with claim 9,21-chloro-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregn-4-ene-3,20-dione.16. A steroid in accordance with claim 9,21-chloro-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.17. A steroid in accordance with claim 9,21-chloro-9-fluoro-11β,17a-dihydroxy-16β-methoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.18. A steroid in accordance with claim 9,21-chloro-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.19. A steroid in accordance with claim 9,21-chloro-9-fluoro-11β-hydroxy-16β,17a-dimethoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.20. A steroid in accordance with claim 9,21-(acetyloxy)-16β-ethoxy-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.21. A steroid in accordance with claim 9,21-(acetyloxy)-16β,17a-diethoxy-9-fluoro-11β-hydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.22. A steroid in accordance with claim 9,21-(acetyloxy)-9-fluoro-11β-hydroxy-16β,17a-dimethoxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.23. A steroid in accordance with claim 9,21-chloro-16β-(1,1-dimethylethoxy)-9-fluoro-11β,17a-dihydroxy-D-homo-17-oxapregna-1,4-diene-3,20-dione.24. A steroid in accordance with claim 9,21-chloro-9-fluoro-11β-hydroxy-16β,17a-bis-(1-methylethoxy)-D-homo-17-oxapregna-1,4-diene-3,20-dione.25. A steroid in accordance with claim 9,21-chloro-9-fluoro-11β,17a-dihydroxy-16β-(1-methylethoxy)-D-homo-17-oxapregna-1,4-diene-3,20-dione.